title: Topogenesis and homeostasis of fatty acyl-CoA reductase 1.
abstract: Peroxisomal fatty acyl-CoA reductase 1 (Far1) is essential for supplying fatty alcohols required for ether bond formation in ether glycerophospholipid synthesis. The stability of Far1 is regulated by a mechanism that is dependent on cellular plasmalogen levels. However, the membrane topology of Far1 and how Far1 is targeted to membranes remain largely unknown. Here, Far1 is shown to be a peroxisomal tail-anchored protein. The hydrophobic C terminus of Far1 binds to Pex19p, a cytosolic receptor harboring a C-terminal CAAX motif, which is responsible for the targeting of Far1 to peroxisomes. Far1, but not Far2, was preferentially degraded in response to the cellular level of plasmalogens. Experiments in which regions of Far1 or Far2 were replaced with the corresponding region of the other protein showed that the region flanking the transmembrane domain of Far1 is required for plasmalogen-dependent modulation of Far1 stability. Expression of Far1 increased plasmalogen synthesis in wild-type Chinese hamster ovary cells, strongly suggesting that Far1 is a rate-limiting enzyme for plasmalogen synthesis.
authors.affiliation: From the Department of Biology, Faculty of Sciences.
authors.forename: Masanori
authors.initials: M
authors.lastname: Honsho
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Asaoku
authors.forename: Keiko
authors.initials: K
authors.lastname: Fukumoto
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiki
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D061986:MCF-7 Cells; D020675:Peroxisomes / Q000378:metabolism; D010955:Plasmalogens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary
chemical_list: C493805:FAR2 protein, human; D010955:Plasmalogens; D000445:Aldehyde Oxidoreductases; C493803:FAR1 protein, human
keywords: Ether Lipid; Lipid Ether; Peroxisomes; Plasmalogen; Protein Stability; Protein Targeting